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Gastric GDF15 levels are regulated by age, sex, and nutritional status in rodents and humans

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Abstract

Aim

Growth differentiation factor 15 (GDF15) is a stress response cytokine that has been proposed as a relevant metabolic hormone. Descriptive studies have shown that plasma GDF15 levels are regulated by short term changes in nutritional status, such as fasting, or in obesity. However, few data exist regarding how GDF15 levels are regulated in peripheral tissues. The aim of the present work was to study the variations on gastric levels of GDF15 and its precursor under different physiological conditions, such as short-term changes in nutritional status or overfeeding achieved by HFD. Moreover, we also address the sex- and age-dependent alterations in GDF15 physiology.

Methods

The levels of gastric and plasma GDF15 and its precursor were measured in lean and obese mice, rats and humans by western blot, RT-PCR, ELISA, immunohistochemistry and by an in vitro organ culture system.

Results

Our results show a robust regulation of gastric GDF15 production by fasting in rodents. In obesity an increase in GDF15 secretion from the stomach is reflected with an increase in circulating levels of GDF15 in rats and humans. Moreover, gastric GDF15 levels increase with age in both rats and humans. Finally, gastric GDF15 levels display sexual dimorphism, which could explain the difference in circulating GFD15 levels between males and females, observed in both humans and rodents.

Conclusions

Our results provide clear evidence that gastric GDF15 is a critical contributor of circulating GDF15 levels and can explain some of the metabolic effects induced by GDF15.

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Funding

This study has been funded by Instituto de Salud Carlos III (ISCIII) through the grant number PI22/00202 (L.M.S.) and PI21/01216 (OA-M) and co-funded by the European Union. GAIN-XUNTA de Galicia, Proyectos de Excelencia [IN607D 2023/02 (M.Q.), IN607D-2022-07 (O.A.-M.) and IN607D-2022-04 (L.M.S.)]; Ministerio de Ciencia e Innovación and “FEDER” PID2022-142084OA-100 (M.Q.); Fundación de la Sociedad Gallega de Endocrinología y Nutrición (OA-M); Centro de Investigación Biomédica en Red (CIBER) de Fisiopatología de la Obesidad y Nutrición (CIBERobn). CIBERobn is an initiative of the Instituto de Salud Carlos III (ISCIII) of Spain, which is supported by FEDER funds; E.P. and RP-L hold a IDIS fellowship. OA-M and MQ were funded by a research contract Miguel Servet (CP20/00146 CP21/00108 respectively) from the ISCIII. The data figures were generated by using BioRender.com.

Author information

Author notes

  1. V. Pena-Leon and R. Pérez-Lois contributed equally to this work.

Authors and Affiliations

  1. Grupo Fisiopatología Endocrina, Área de Endocrinología, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (CHUS/SERGAS), Santiago de Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, Spain

    V. Pena-Leon, R. Perez-Lois, M. Villalon, C. Folgueira, S. Barja-Fernández, M. Quiñones & L. M. Seoane

  2. Translational Endocrinology Group, Endocrinology Section, Instituto de Investigación Sanitaria de Santiago de Compostela, Complexo Hospitalario Universitario de Santiago (IDIS/CHUS), Santiago de Compostela, Spain

    E. Prida & O. Al-Massadi

  3. Servicio de Cirugía General y del Aparato Digestivo, CHUS7SERGAS Santiago de Compostela, Rua R Baltar s/n, 15706, Santiago de Compostela, Spain

    J. Baltar & F. Santos

  4. Hormone Laboratory, Department of Biochemistry and Pharmacology, Haukeland University Hospital, 5201, Bergen, Norway

    J. Fernø

  5. Departamento de Ciencias Morfologicas, Facultad de Medicina, USC, Complejo Hospitalario de Santiago (CHUS/SERGAS), Santiago de Compostela, Spain

    T. García-Caballero

  6. Departamento de Fisiología, Instituto de Investigación Sanitaria de Santiago de Compostela, CIMUS, University of Santiago de Compostela, 15782, Santiago de Compostela, Spain

    R. Nogueiras

  7. CIBER de Fisiopatología de la Obesidad y la Nutrición, Instituto de Salud Carlos III, Spain, Compostela, Travesía da Choupana s/n, 15706, Santiago de Compostela, Spain

    R. Nogueiras, M. Quiñones, O. Al-Massadi & L. M. Seoane

Authors
  1. V. Pena-Leon
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  2. R. Perez-Lois
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  3. M. Villalon
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  4. C. Folgueira
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  5. S. Barja-Fernández
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  6. E. Prida
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  7. J. Baltar
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  8. F. Santos
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  9. J. Fernø
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  11. R. Nogueiras
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  13. O. Al-Massadi
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  14. L. M. Seoane
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Contributions

Conceptualization, OA-M, LMS, formal Analysis, VP-L, RP-L, investigation, VP-L, RP-L, MV, CF, SB-F, EP, TG-C, JB, FS, MQ; writing–original draft, VP-L, RN, OA-M, and LMS; writing–review and editing, VP-L, JF, RN, MQ, OA-M and LMS; funding acquisition, LMS, OA.

Corresponding authors

Correspondence to O. Al-Massadi or L. M. Seoane.

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Conflict of interest

The authors declare no conflict of interest. The authors declare they have no financial interests.

Research involving human participants and/or animals

This study was conducted in accordance with the guidelines in the Declaration of Helsinki and approved by the Ethics and Research Committee of the Autonomous Community of Galicia Community under code 2013/256.

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All samples were obtained with the informed consent of all included patients.

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Pena-Leon, V., Perez-Lois, R., Villalon, M. et al. Gastric GDF15 levels are regulated by age, sex, and nutritional status in rodents and humans. J Endocrinol Invest 47, 1139–1154 (2024). https://doi.org/10.1007/s40618-023-02232-y

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